The invention concerns the preparation of diisopinocampheylborane. The invention also relates to the use of a crude diisopinocampheyl borane product in the reduction of prochiral ketones.
Previously, diisopinocampheylborane was prepared and isolated by crystallization prior to its conversion to the active reducing agent diisopinocampheylchloroborane. This intermediate is highly sensitive to both oxygen and water, thus complicating its isolation.
Isolation by crystallization had the effect of increasing the enantiomeric purity of the reagent to &gt;99%, starting from pinene of an optical purity of approximately 90%. This upgrading of the enantiomeric purity of the reducing reagent via crystallization was deemed critical for obtaining maximum enantioselectivity in the reduction of ketones to alcohols. See Brown, H. C.; Park, W. S.; Cho, B. T.; Ramachandran, P. V. J. Org. Chem., 1987, 52, 5406 and references therein; Brown, H. C.; Chandrasekharan, J.; Ramachandran, J.; Ramachandran, P. V. J. Org. Chem. 1986, 51, 3394; Srebnik, M. Ramachandran, P. V.; Brown, H. C. J. Org. Chem., 1988, 53, 2916; and Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem. Soc. 1988, 1539.
The present invention demonstrates this previously held tenet to be false. Diisopinocampheylborane is prepared in-situ, without isolation or discrete purification, and yet surprisingly performs in an equal manner to isolated reagent. This represents a major process advantage since both the diisopinocampheylborane and the diisopinocampheylchloroborane are highly reactive reagents, sensitive to both oxygen and water. Thus handling of these reagents, which would be necessitated during isolation, presents difficulty.
The present invention also concerns the use of a crude diisopinocampheylborane product in the preparation of the chiral alcohols such as those of the intermediate compounds of Formula B. ##STR2##
Use of diisopinocampheyl chloroborane in the preparation of the chiral alcohols is described in the references cited above. Use of diisopinocampheyl chloroborane in the preparation of the chiral hydroxides of Formula B is described in co-pending applications U.S. Ser. Nos. 546,486 abandoned and 546,486 filed by Shinkai et al., Jun. 29, 1990 U.S. Pat. 509,9033. Intermediate compounds of Formula B are useful in making PAF antagonists of Formula I ##STR3##
Platelet-activating factor (PAF) has recently been identified as an acetyl glyceryl ether phosphorylcholine (AGEPC), i.e., 1-0-hexadecyl/octadecyl-2acetyl-sn-glyceryl-3-phosphocholione (Hanahan D. J., etal., J. Biol. Chem. 255:5514, 1980). PAF has been linked to various biological activities and pathways making it one of the important mediators responsible for a variety of physiological processes including activation or coagulation of platelets, pathogenesis of immume complex deposition, smooth muscle contraction, inflammation, hypotension, shock, pain, edema as well as respiratory, cardiovascular and intravascular alterations. These physiological processes are in turn associated with a large group of diseases, for example, inflammatory disease, cardiovascular disorder, hypotension, shock, psoriasis, allergic and skin diseases, asthma, lung edema, peptic or stomach ulcer, dental pain, and adult respiratory distress syndrome.
Some compounds of formula (I) as well as their utility as PAF antagonists and their method of preparation are disclosed in U.S. Pat. No. 4,539,335 which issued on Sep. 3, 1985; E.P. 0 199 324, which published on Oct. 29, 1986; E.P. 0 322 033, published on Jun. 28, 1989; and co-pending U.S. application Ser. No. 362919, filed Jun. 8, 1989, all of which are incorporated by reference.
U.S. Ser. No. 546,486, filed Jun. 29, 1990, which reference is hereby incorporated by reference discloses a process of making intermediate butyrolactone of Formula D. That process is outlined in Scheme 1. ##STR4##
In Step A, an in situ prepared acyl anion equivalent, Compound E, which is derived from a substituted benzaldehyde is chemoselectively added to an .alpha.,.beta.-unsaturated ester, to yield Compound A. This single transformation assembles the requisite carbon framework from commercially available precursors. In Step B an enantioselective reduction utilizes .beta.-chlorodiisopinocampheyl borane in an unprecedented manner to produce an optically enriched 4-aryl-4-hydroxy-butanoate, Compound B. In Steps C to D conversion of Compound B to the title lactone Compound D is accomplished via a novel, internally assisted saponification followed by a mild acid catalyzed lactonization. Both saponification and lactonization are effected without racemization. Thereafter, controlled crystallization of Compound D efficiently enriches the optical purity to greater than 99.5%.
It is to be noted, however, that U.S. Ser. No. 546,486 utilized a preformed and purified diisopinocampheyl chloroborane.
In sharp contrast the instant process of making a compound of Formula D, comprehends the novel unobvious approach whereby the reactions can be accomplished without the heretofor recognized need to resort to extensive purification.